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Abstract Number: 1093

Activation of Syk-Btk Signal in Peripheral Blood B Cells in Patients with Rheumatoid Arthritis: A Potential Target for Abatacept Therapy

Shigeru Iwata1, Shingo Nakayamada2, Shunsuke Fukuyo1, Sheau-Pey Wang1, Satoshi Kubo2, Maiko Yoshikawa1, Kazuyoshi Saito3 and Yoshiya Tanaka3, 1The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan, 2First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan, 3The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Abatacept and rheumatoid arthritis (RA), B cell targeting, BTK, SYK

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Session Information

Date: Monday, November 9, 2015

Session Title: B cell Biology and Targets in Rheumatolid Arthritis and other Autoimmune Disease Poster

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: B cells play a pivotal role in the pathogenesis of autoimmune diseases. Although Syk function as a key molecule in BCR signaling, the pathological role of Syk in B cells in RA remains unclear. The purpose of this study was to assess the relevance of activation of Syk in B cells to RA pathology and responsiveness to treatment with biologics.

Methods: Healthy subjects (n=36) and patients with moderate or severe RA disease activity (n=70) were studied. The phosphorylation of Syk in peripheral blood B cells was measured by flow cytometry, and the correlation with clinical characteristics and changes after administration of biological products were evaluated.

Results: Syk phosphorylation in B cells was significantly higher in RA patients compared with the control (p-Syk-positive CD19+ B cells (%): control, 11.9±8.2; RA, 27.7±23.2, p=0.0019). The expression levels of p-Syk in all different treatment groups of RA patients were significantly higher than the control (control; 10.7±1.3%, treatment-naïve RA (n=12); 21.6±7.7%, MTX-treated (n=36); 24.8±3.3%, MTX+biologics-treated (n=9); 30.8±10.0%, p=0.0036). Although Btk is well-known as downstream of Syk, Btk phosphorylation in B cells was also higher in patients with RA compared with the control (mean MFI of p-Btk in CD19+ B cells: control, 144±73.4; RA, 224±171, p=0.031). Syk phosphorylation was significantly higher in B cells of patients strongly positive for ACPA (p-Syk-staining among CD19+ B cells (%): negative for ACPA, 22.2±24.9; positive, 19.5±21.5; strongly positive, 32.6±23.5; p=0.0335), but not correlated with indexes of RA disease activity, such as tender joints, swollen joints, CRP, ESR, MMP-3, DAS28-CRP, DAS28-ESR, CDAI, and SDAI. Autoantibody production by B cells requires the involvement of T cells and abatacept can inhibit T cell activation. Based on this background, we hypothesized that abatacept inhibits Syk phosphorylation in B cells. Interestingly, the rate p-Syk-positive cells among CD19+ B cells diminished from 21.4±30.9 to 3.3±3.8 (from week 0 to week 24, p=0.0341) in the abatacept group, and from 30.0±23.1 to 42.0±34.8 (p=0.1255) in the TNF inhibitors group. Although Th1 cells (CD4+CXCR3+ cells) were not changed, abatacept significantly reduced the proportion of Tfh cells (CD4+CXCR5+PD-1+ cells) from 5.7±5.7 at week 0 to 3.4±4.7 % at week 4 (p=0.0206).

Conclusion: Our results demonstrated that significantly high levels of Syk phosphorylation in B cells were strongly related to ACPA in RA patients. Our data suggested that abatacept seems to inhibit Syk-Btk signal in B cells as well as development of T follicular helper cells, highlighting the relevance of B-T cell interaction as a potential target of abatacept therapy in RA.


Disclosure: S. Iwata, None; S. Nakayamada, None; S. Fukuyo, None; S. P. Wang, None; S. Kubo, None; M. Yoshikawa, None; K. Saito, None; Y. Tanaka, Mitsubishi-Tanabe, Eisai, Chugai, Abbott Japan, Astellas, Daiichi-Sankyo, Abbvie, Janssen, Pfizer, Takeda, Astra-Zeneca, Eli Lilly Japan, GlaxoSmithKline, Quintiles, MSD, Asahi-Kasei, 5,Bristol-Myers, Mitsubishi-Tanabe, Abbvie, MSD, Chugai, Astellas, and Daiichi-Sankyo, 2.

To cite this abstract in AMA style:

Iwata S, Nakayamada S, Fukuyo S, Wang SP, Kubo S, Yoshikawa M, Saito K, Tanaka Y. Activation of Syk-Btk Signal in Peripheral Blood B Cells in Patients with Rheumatoid Arthritis: A Potential Target for Abatacept Therapy [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/activation-of-syk-btk-signal-in-peripheral-blood-b-cells-in-patients-with-rheumatoid-arthritis-a-potential-target-for-abatacept-therapy/. Accessed February 3, 2023.
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